1. Field of the Invention
The present invention relates to a transnasal anticonvulsive pharmaceutical composition. More specifically, the present invention relates to an anticonvulsive pharmaceutical composition for transmucosal delivery of diazepam having improved solubility and transmucosal permeability of diazepam.
2. Description of the Related Art
Status epilepticus (SE), a prolonged epileptic seizure, refers to a serious neurological emergency which may lead to the mortality rate of from 3 to 35% in the total SE patients. The primary goal of the treatment of SE resides in the rapid management of pathological seizure activity since the longer that an episode of status epilepticus remains untreated, the more difficult it is to control and the greater the risk of permanent brain damage. Thus, critical to the management of the patients is a prompt treatment involving administration of a pharmaceutical composition in the form of a proper pharmaceutical formulation containing an active drug ingredient at an adequate dose.
Currently, several drug regimens known in the art have been proven to be efficacious in the treatment of status epilepticus. Diazepam is one of the most widely used benzodiazepines for this purpose. Intravenous (IV) administration of anticonvulsants, such as diazepam, is the most rapid way to suppress epileptic convulsions. However, other routes of administration may be highly desirable when intravenous administration is inconvenient or is delayed, for instance, because of technical difficulties such as requirements for sterile equipment and trained personnel, and because of the probable development of phlebitis. In addition, intravenous administration of such medication is often associated with hypotension, cardiac dysrhythmia or central nervous system (CNS) depression. In this connection, Moolenaar et al (Int. J. Pharm., 5: 127-137) have attempted an administration of diazepam to humans via several other routes such as intramuscular injection, oral tablet and rectal solution. Only the rectal administration was found to provide a fairly rapid absorption of the drug and thus, it might be considered as an alternative administration route to IV injection. However, the rectal route is a very inconvenient way of drug administration particularly in the patients requiring emergency treatment.
U.S. Pat. No. 4,863,720, issued to Burghardt, discloses a sublingual sprayable pharmaceutical preparation wherein the active drug ingredient can be a benzodiazepine. Such preparations preferably contain polyethylene glycol (PEG), and ethanol, di- and/or triglycerides of fatty acids and a pharmaceutically acceptable propellant gas are required components.
More recently, it appears that the nasal mucous membrane offers a practical route of administration for therapeutic effects of various medicinal substances. Intranasal administration has an advantage in that drugs of interest may be administered readily and simply to achieve systemic or topical effects, as required. However, the major problem associated with intranasal drug administration is the fact that most drug molecules diffuse poorly and slowly through the nasal mucous membrane and thus the desired level of the therapeutic agent cannot be achieved by means of simple transnasal administration. An additional limitation concerning nasal administration is that it is typically limited to a small volume. That is, it is generally not possible to administer the drug at a dose level of more than approximately 150 μl per nostril. Volumes of the formulation exceeding the above level will be drained out and swallowed into the pharynx. Hence, it is necessary that the required dose of the drug is provided in such a volume.
In addition, it is difficult to develop a pharmaceutical formulation of diazepam suitable for nasal spray administration, due to a low solubility of diazepam in water which is conventionally used to dissolve the drug for administration. Therefore, there is a strong need for the development of a solvent vehicle which can dissolve the desired medication, i.e. diazepam, to a high concentration, while not causing irritability to the nasal mucosa.
The intranasal drug absorption rate can be increased by co-administration of the desired drug with a chemical adjuvant or a penetration enhancer. For example, Lau and Slattery (Lau et al., Int. J. Pharm., 54: 171-174 (1989b)) have attempted an intranasal administration of a benzodiazepine such as diazepam by dissolving it in a variety of solvents such as triacetin, dimethylsulfoxide, PEG 400, Cremophor EL, Lipal-9-LA, isopropyl adipate and Azone.
However, it was found that, while the majority of the solvents dissolved diazepam to the desired concentration, the resulting solutions were too irritating to be used for transnasal administration. Cremophor EL was found to have the lowest irritability for nasal mucosal tissues, but the nasal absorption of the drug with the use of such a vehicle in humans was rather slow (Tmax of 1.4 hours) and the peak concentration was low, as compared to that observed after IV administration.
In recent years, Li et al (International Journal of Pharmaceutics Vol. 237, pp 77-85, 2002) have disclosed microemulsions for rapid-onset transnasal delivery of diazepam. Further, U.S. Pat. No. 6,627,211 discloses a composition for transnasal administration of diazepam via a solubilized preparation wherein diazepam is dissolved using an aliphatic alcohol, glycol and water as a polar solvent. In addition, US Patent Application No. 2005-0002987 A1 discloses a microemulsion for transnasal administration of diazepam wherein diazepam is dissolved using an emulsion vehicle comprised of equal amounts of a fatty acid and water with the remainder being a hydrophilic surfactant, and a polar solvent, e.g. glycol.
The pharmaceutical preparation disclosed in U.S. Pat. No. 6,627,211 is a solubilized preparation wherein an aliphatic alcohol, a glycol as a polar solvent, and ethanol are used in large amounts. According to this art, when a small amount of diazepam is contained in the preparation, it is possible to enhance the transmucosal permeability of diazepam. However, when the content of diazepam is increased to a level of more than 2.5% as in Example 4 therein, thus resulting in poor dissolution of diazepam and consequently requiring transnasal administration of diazepam in a large volume so as to deliver an effective concentration of the drug, this may lead to the problems associated with a need for repeated administration because a possible maximum amount of intranasal administration is limited to within a level of 150 μl, as discussed hereinbefore. Further, the preparation disclosed in US Patent Application No. 2005-0002987 A1 is a microemulsion preparation using equal amounts of a fatty acid ester and water and large amounts of a hydrophilic surfactant, and a polar solvent, e.g. glycol and an alcohol. According to this art, the concentration of diazepam in the preparation is 41 mg/mL and therefore diazepam can be dissolved up to an about 4.1% concentration, thus resulting in an increased solubility of diazepam as compared to the preparation of U.S. Pat. No. 6,627,211. However, this pharmaceutical formulation suffers from a decreased transmucosal permeability, and therefore also requires transnasal administration of diazepam at a large volume so as to deliver an effective concentration of the drug, thus causing an inconvenience associated with a need of repeated administration. There is thus a need for a pharmaceutical composition for transmucosal administration of diazepam having improved solubility and transmucosal permeability of diazepam. Such compositions and a method of treatment are provided in accordance with the present invention.